Moderate CYP3A4 Inhibitor Research Articles

The Pharmacokinetics of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone.

Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.

Coadministration of bedaquiline and pyrifazimine reduce exposure to toxic metabolite N-desmethyl bedaquiline.

Background: A new, effective anti-tuberculosis (TB) regimen containing bedaquiline (BDQ) and pyrifazimine (TBI-166) has been recommended for a phase IIb clinical trial. Preclinical drug-drug interaction (DDI) studies of the combination of BDQ and TBI-166 have been designed to support future clinical trials. In this study, we investigated whether a DDI between BDQ and TBI-166 affects the pharmacokinetics of BDQ. Methods: We performed in vitro quantification of the fractional contributions of the fraction of drug metabolism by individual CYP enzymes (f m) of BDQ and the inhibition potency of key metabolic pathways of TBI-166. Furthermore, we conducted an in vivo steady-state pharmacokinetics study in a murine TB model and healthy BALB/c mice. Results: The in vitro f m value indicated that the CYP3A4 pathway contributed more than 75% to BDQ metabolism to N-desmethyl-bedaquiline (M2), and TBI-166 was a moderate (IC50 2.65µM) potential CYP3A4 inhibitor. Coadministration of BDQ and TBI-166 greatly reduced exposure to metabolite M2 (AUC0-t 76310 vs 115704hng/mL, 66% of BDQ alone), whereas the exposure to BDQ and TBI-166 did not changed. The same trend was observed both in healthy and TB model mice. The plasma concentration of M2 decreased significantly after coadministration of BDQ and TBI-166 and decreased further during treatment in the TB model. Conclusions: In conclusion, our results showed that the combination of BDQ and TBI-166 significantly reduced exposure to the toxic metabolite M2 by inhibiting the activity of the CYP3A4 pathway. The potential safety and efficacy benefits demonstrated by the TB treatment highly suggest that coadministration of BDQ and TBI-166 should be studied further.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

Effects of Omeprazole and Verapamil on the Pharmacokinetics, Safety, and Tolerability of Mavacamten: Two Drug-Drug Interaction Studies in Healthy Participants.

Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor) on the pharmacokinetics, safety, and tolerability of mavacamten. In the omeprazole study, healthy participants received mavacamten 15mg alone or with a 31-day course of omeprazole 20mg once daily. In the verapamil study, healthy participants received mavacamten 25mg alone or with a 28-day course of verapamil 240mg once daily. In the omeprazole study, 27 of 29 randomized participants completed the study. Nine participants receiving mavacamten alone were normal metabolizers (NMs) of CYP2C19 substrates, and 6 were rapid metabolizers; 8 NMs and 6 rapid metabolizers received mavacamten + omeprazole. In both studies, mavacamten showed no safety signals and was generally well tolerated. Overall mavacamten exposure (area under the plasma concentration-time curve) increased by approximately 50% with omeprazole coadministration; maximum observed concentration (Cmax ), time to Cmax , and elimination half-life were not affected appreciably. In the verapamil study, 25 of 26 randomized participants received the study drug(s) and were included in the pharmacokinetic analyses; 24 completed the study. In the pharmacokinetic population, 12 participants received mavacamten alone (11 NMs, 1 poor metabolizer) and 13 received mavacamten + verapamil (7 NMs, 4 intermediate metabolizers, 2 poor metabolizers). Following verapamil coadministration in NMs and intermediate metabolizers, mavacamten area under the plasma concentration-time curve was minimally increased (by less than 20%), and Cmax was modestly increased (by 52%). These results suggest that mavacamten can be coadministered with weak CYP2C19 and moderate CYP3A4 inhibitors.

Physiologically-based pharmacokinetic modeling for optimal dosage prediction of olaparib when co-administered with CYP3A4 modulators and in patients with hepatic/renal impairment

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (Cmax) and trough concentration (Ctrough) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold Cmax (< 12,500 ng/mL) and Ctrough (772–2500 ng/mL). The population PBPK model for OLA was successfully developed and validated, demonstrating good consistency with clinically observed data. The ratios of predicted to observed values for Cmax and Ctrough fell within the range of 0.5 to 2.0. When OLA was co-administered with a strong or moderate CYP3A4 inhibitor, the recommended dosing regimens should be reduced to 100 mg BID and 150 mg BID, respectively. Additionally, the PBPK model also suggested that OLA could be not recommended with a strong or moderate CYP3A4 inducer. For patients with moderate hepatic and renal impairment, the dosing regimens of OLA were recommended to be reduced to 200 mg BID and 150 mg BID, respectively. In cases of severe hepatic and renal impairment, the PBPK model suggested a dosing regimen of 100 mg BID for OLA. Overall, this present PBPK model can determine the optimal dosing regimens for various clinical scenarios involving OLA.

Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype.

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ). Following model verification, the PBPK model was used to explore the effects of strong CYP3A4 and CYP2C19 inducers, and strong, moderate, and weak CYP2C19 and CYP3A4 inhibitors on mavacamten pharmacokinetics (PK) in a healthy population, with the effect of CYP2C19 phenotype predicted for poor, intermediate, normal, and ultrarapid metabolizers. The PBPK model met the acceptance criteria for all verification simulations (> 80% of model-predicted PK parameters within 2-fold of those observed clinically). A weak induction effect was predicted when mavacamten was administered with a strong CYP3A4 inducer in poor metabolizers. Moderate reductions in mavacamten exposure were predicted with a strong CYP2C19/CYP3A4 inducer in all CYP2C19 phenotypes. Except for the effect of strong CYP2C19 inhibitors on ultrarapid metabolizers, steady-state area under plasma concentration-time curve and maximum plasma concentration values were weakly affected (< 2-fold) or not affected (< 1.25-fold), regardless of CYP2C19 phenotype. In conclusion, a fit-for-purpose PBPK model was developed and verified, which accurately predicted the available clinical data and was used to simulate the potential impact of CYP induction and inhibition on mavacamten PKs, stratified by CYP2C19 phenotype.

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (<1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis.

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.

Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2 and 3 Clinical Trials.

Following the decade long clinical investigation, venetoclax has accrued PK data across multiple populations and widely-ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population pharmacokinetic (popPK) modeling. Plasma concentration-time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from nine indications and healthy volunteers. A nonlinear mixed-effect model was developed. Covariates were evaluated with full covariate modeling approach. A two-compartment model with three transit absorption compartments described the data well. The impact of moderate and strong CYP3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution (V2/F), food effect on relative bioavailability (F1) and dose non-linearity was confirmed. Newly identified covariate effects include 48% lower CL/F in severe hepatic impairment subjects, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least one strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross-indication popPK model with improved absorption phase characterization was developed. Covariate analyses suggested lower CL/F for severe hepatic impairment subjects and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor. This article is protected by copyright. All rights reserved.

Evaluating the impact of co-administered drug and disease on ripretinib exposure: A physiologically-based pharmacokinetic modeling approach

Ripretinib, as an oral kinase inhibitor, has been approved to treat advanced gastrointestinal stromal tumors (GIST) and is often used in combination with other drugs to slow disease progression, thus potential drug-drug Interactions (DDIs) and drug-disease interactions (DDZIs) have received much attention. To guide clinical rational drug use, this study assessed the effect of co-administered drugs and diseases on ripretinib exposure. Simcyp® Simulator was used to develop the physiologically-based pharmacokinetic (PBPK) model of ripretinib, which was validated and refined with clinical data. We then examined the impact of several CYP3A4 inhibitors and inducers as well as different diseases on ripretinib exposure using the validated model. In the DDI simulation, moderate CYP3A4 inhibitors and inducers changed the exposure of ripretinib by 1.25–2 fold. In hepatic impairment (HI), the simulation showed that ripretinib's AUC increased by 32%, 100%, and 152% for Child-Pugh A, B, and C classification while Cmax increased by 2%, 10%, and 15%, respectively. In renal impairment (RI), the model-simulated AUC in moderate and severe RIs increased by 27% and 20%. In conclusion, PBPK models demonstrated quantitative prediction of ripretinib's pharmacokinetic changes under varying conditions that might be useful for its rational use.

Population Pharmacokinetic and Exposure-Safety Analyses of Ibrutinib for the Treatment of Chronic Graft-Versus-Host Disease.

The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points.

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models.

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a "perpetrator," would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a "victim" or "perpetrator".

A phase 1, open-label, randomized drug–drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

Antifungal Choice during Intravenous to Oral Cyclosporine Switch Effects Bioavailability in Patients Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Cyclosporine is a key drug during hematopoietic stem cell transplantation for the prevention of Graft-versus-Host disease with the potential for involvement in drug-drug interactions. We conducted this study to evaluate the effects of antifungals on cyclosporine blood levels and biavailability values. Material and Methods: Patients who had allogeneic hematopoietic stem cell transplantation with normal kidney and liver function and no other drug-drug interactions that could affect cyclosporine blood levels were included in the study. Patients were categorized into moderate (fluconazole) and strong (voriconazole, posaconazole) CYP3A4 inhibitor antifungal users and non-azole (amphotericin B, caspofungin) users. We collected intravenous and oral cyclosporine blood concentrations and doses during cyclosporine administration route changes and evaluated the effects of them according to antifungal groups. Results: We included 94 patients. The moderate and strong CYP3A4 inhibitor user numbers were 54 and 22, respectively. 18 patients with non-azole antifungal prescriptions were included. ANOVA revealed that there was a statistically significant difference in blood corrected concentrations (p<0.0001). The mean oral dose to intravenous dose ratio was 1.44 and 1.53 for the strong and moderate CYP3A4 inhibitor groups, respectively. This ratio was 1.51 for non-azole antifungal users. The median cyclosporine concentrations were higher after switching to oral cyclosporine in three antifungal groups. The highest mean cyclosporine concentration was 378,45 ng/mL and was obtained from patients with strong CYP3A4 inhibitor antifungals. The lowest mean cyclosporine concentration was observed in patients who were prescribed non-azole antifungals, which was subtherapeutic at 165,95 ng/mL. Bioavailability values were 1.17, 0.97, and 0.9 for moderate inhibitor, strong inhibitor, and non-azole users, respectively. In our study, the general oral dose to intravenous dose ratio regardless of the antifungal choice was 1.50. Despite having the lowest dose ratio (1.44), the highest bioavailability (1.17) was achieved by strong CYP3A4 inhibitor users, and nine of them experienced supratherapeutic cyclosporine levels. After applying a 1.53 dose ratio, the highest mean dose ratio among groups, the number of patients with supratherapeutic cylosporine levels increased to twenty-two from six. Eight patients with non-azole antifungal prescriptions still experienced subtherapeutic cyclosporine blood levels after the initiation of a 1.51 mean dose ratio, which suggests non-azole users may need higher oral cyclosporine doses (Figure 1). Conclusion: Cyclosporine is a gold medicine during the allogeneic hematopoeitic stem cell trasnplantation process. Concomitant antifungal therapy affects cyclosporine blood levels during cyclosporine administration.Patients who are prescribed non-azole antifungals such as caspofungin and amphotericin B are at an increased risk of Graft-versus-Host disease due to the lack of therapeutic cyclosporine levels. Patients with azole antifungals may face cyclosporine toxicities during cyclosporine route change due to hepatic enzyme inhibitions. For patients with strong CYP3A4 inhibitor antifungals such as voriconazole and posaconazole, the oral dose to intravenous dose ratio should be adjusted carefully to avoid toxicity. Fluconazole, a moderate CYP3A4 inhibitor, causes a wide range of cyclosporine blood levels, which makes it hard to advise strict dose ratios. Because patient responses to enzyme inhibitors varied in our study, we advise taking precautions on an individual basis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of Isavuconazole on Plasma and CSF Levels of Ibrutinib and Plasma Levels of Liposomal Doxorubicin Among Patients Receiving Teddi-R for CNS Lymphoma

Background: Ibrutinib is an oral BTK inhibitor that is highly effective for B-cell lymphomas and chronic graft versus host disease. Escalating doses of ibrutinib were highly active and achieved good CNS penetration when added to temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) in primary CNS lymphoma (PCNSL) but was associated with aspergillosis (Lionakis Cancer Cell 2017). To prevent aspergillosis, we added the antifungal agent isavuconazole (isa) to the TEDDI-R regimen, but it is a moderate inhibitor of CYP3A4 and inhibits ibrutinib clearance. We performed a new dose escalation study of ibrutinib with concomitant isavuconazole and TEDD-R in PCNSL with a dose expansion cohort. In a separate study, we tested fixed doses of ibrutinib with TEDD-R in secondary CNS lymphoma (SCNSL) with pharmacokinetic (PK) sampling from plasma and cerebrospinal fluid (CSF). Herein we present the PK of ibrutinib in plasma and CSF from both ongoing studies along with plasma PK of liposomal doxorubicin. Methods: Patients with untreated and relapsed/refractory PCNSL enrolled onto the phase 1 trial of TEDDI-R with isa in a standard 3+3 fashion testing three dose levels of ibrutinib: DL1=280 mg, DL2=420 mg, and DL3=560 mg. Patients with untreated and relapsed/refractory SCNSL were enrolled onto a phase 2 trial of TEDDI-R with isa and a fixed dose of ibrutinib 560 mg. Isa was started ≥3 days before ibrutinib and continued throughout combination therapy of 4 to 6 cycles. At the first dose of ibrutinib, patients with PCNSL underwent plasma and CSF sampling at the following timepoints: pre-dose, then 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10-18 hr (one sample in this timeframe), and 24 hr post-dose. Patients with SCNSL underwent plasma sampling at pre-dose, 1 hr, and 10-18 hr (one sample in this timeframe) after the first ibrutinib dose. All patients also had steady-state (≥4 prior ibrutinib doses) plasma and CSF sampling at pre-dose and 2 hr post-dose. Plasma sampling for liposomal doxorubicin (dose range 30-50 mg/m2) occurred at pre-dose and at 5-8 hours post-dose. Concentrations were measured using LC-MS/MS (Frontage Laboratories and NCI). PK parameters were estimated using non-compartmental methods. Results: 55 consecutive patients (30 PCNSL, 25 SCNSL) were included for analysis. Among the 30 patients with dense first-dose sampling, the Tmax was 2.05 hr (SD 1.06, n=30), T1/2 8.3 hr (median 6.2 hr, SD 6.4, n=26), volume of distribution 13121 L (median 10756, SD 11422, n=24), and clearance 1560 L/hr (median 1093, SD 1397, n=24) (patients with r2<0.9 excluded). There was wide interpatient variability in ibrutinib PK. In both the plasma and CSF, ibrutinib 560 mg + isa had a higher AUC, Cmax, and steady-state peak concentration than 560 mg alone. Compared to 700 mg and 840 mg alone, 560 mg + isa had a similar AUC and Cmax in the plasma, but a higher steady-state peak plasma concentration. In the CSF, 560 mg + isa had a similar AUC and Cmax but higher steady-state peak concentration compared to 700 mg alone, and a higher AUC and Cmax but similar steady-state peak concentration compared to 840 mg alone (Tables 1 and 2). Peak (5-8 hours post-dose) plasma concentrations of liposomal doxorubicin were not significantly different with isa versus without isa (dose-normalized geometric mean ratio 0.94, 95% CI 0.80-1.08, n=82 data points). Conclusions: Isavuconazole increases the plasma and CSF exposure of ibrutinib approximately 2-fold, allowing for similar or improved CNS penetration at 560 mg compared to what was previously observed with ibrutinib 700 mg and 840 mg without isavuconazole. Further development of the TEDDI-R regimen utilizes ibrutinib 560 mg as the target dose along with isavuconazole. Plasma concentrations of liposomal doxorubicin were not significantly affected by isavuconazole. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, and/or spinal cord without evidence of systemic disease. While frontline PCNSL is potentially curable, relapsed PCNSL has a dismal prognosis, particularly if the relapse is within 1 year of frontline therapy. Secondary central nervous system lymphoma (SCNSL) is defined as systemic NHL that has CNS involvement either concurrently or at relapse. There is no standard of care for relapsed CNS lymphoma. Recently, though, novel targeted agents have shown promise. Bruton's tyrosine kinase (BTK) is a key enzyme in the B-cell receptor (BCR) signaling pathway. In some B-cell NHL, BTK is essential for proliferation and survival. The BTK inhibitor (BTKi) ibrutinib is effective for the treatment of both primary and secondary CNS lymphomas with response rates of 68% (CR=45%) and 56% (CR=17%), respectively. Acalabrutinib is an irreversible BTKi that has been evaluated in NHL. Phase 2 trials of acalabrutinib in relapsed/refractory MCL reported an ORR of 80.6% with a CR rate of 39.5%. Importantly, there were no cases of atrial fibrillation and only 1 case of grade 3 or higher gastrointestinal hemorrhage. We hypothesize that acalabrutinib, a more selective BTKi, may be an effective treatment for relapsed CNS lymphomas with fewer complications. Study Design/Methods: This is a multicenter, open-label, single-arm, pilot study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed PCNSL or SCNSL that is open to accrual (NCT04548648). All subjects receive acalabrutinib 100mg every 12 hours until progression or discontinuation of treatment due to an adverse event. Prophylactic administration of the antifungal agent isavuconazole will be mandatory while subjects receive acalabrutinib. This decision is based on cases of invasive aspergillosis in studies evaluating ibrutinib. As a moderate CYP3A4 inhibitor, isavuconazole may increase acalabrutinib levels. Pharmacokinetic studies have shown that coadministration may increase acalabrutinib dosing 2- to 3-fold. We feel that this possible increase in concentration is reasonable given the need for blood-brain-barrier penetration. During the study, 15 evaluable subjects will be enrolled and treated. Response will be assessed via brain magnetic resonance imaging (MRI) after 2, 4, 6, 9, 12, 18 and 24 months. After 24 months, patients will require yearly MRIs for response assessment. The primary endpoint is overall response rate (ORR) at 2 months of therapy. Secondary endpoints include toxicity, complete response (CR) rate, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Key inclusion criteria include: biopsy (can be from initial diagnosis) or MRI findings consistent with B-cell NHL in CNS; ocular and CSF involvement are allowed but there must be a parenchymal mass as well; at least one prior line of therapy; no systemic involvement; ECOG performance status < 2. Key exclusion criteria include: previous BTKi exposure; anticoagulation with warfarin; strong CYP3A4 inhibitor that cannot be stopped; severe hepatic insufficiency; inability to take oral medication. Correlative studies include blood and CSF pharmacokinetic studies of acalabrutinib and its active metabolite, ACP-5862 (collected on day 1 and 8 of cycle 1). Molecular testing will be performed on biopsy samples to evaluate the presence of mutations in the MYD88 and CXCR4 genes. Additionally, the utility of 82Rubidium as a positron emission tomography-radiotracer will be evaluated (at screening and prior to cycle 3 and cycle 7) in the first five subjects at the University of North Carolina who consent to this scan. Mental status and cognitive function will be evaluated with the mini-mental status examination (MMSE) at screening then every 6 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of modeling and simulation to predict the influence of triazole antifungal agents on the pharmacokinetics of zanubrutinib and acalabrutinib.

Background: Bruton’s tyrosine kinase (BTK) inhibitors are commonly used in the targeted therapy of B-cell malignancies. It is reported that myelosuppression and fungal infections might occur during antitumor therapy of BTK inhibitors, therefore a combination therapy with triazole antifungals is usually required. Objective: To evaluate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on the pharmacokinetics of BTK inhibitors (zanubrutinib, acalabrutinib) and to quantify the drug-drug interactions (DDIs) between them. Methods: The physiologically-based pharmacokinetic (PBPK) models were developed based on pharmacokinetic parameters and physicochemical data using Simcyp® software. These models were validated using clinically observed plasma concentrations data which based on existing published studies. The successfully validated PBPK models were used to evaluate and predict potential DDIs between BTK inhibitors and different triazoles. BTK inhibitors and triazole antifungal agents were simulated by oral administration. Results: Simulated plasma concentration-time profiles of the zanubrutinib, acalabrutinib, voriconazole, fluconazole, and itraconazole are consistent with the clinically observed profiles which based on existing published studies, respectively. The exposures of BTK inhibitors increase by varying degrees when co-administered with different triazole antifungals. At multiple doses regimen, voriconazole, fluconazole and itraconazole may increase the area under plasma concentration-time curve (AUC) of zanubrutinib by 127%, 81%, and 48%, respectively, and may increase the AUC of acalabrutinib by 326%, 119%, and 264%, respectively. Conclusion: The PBPK models sufficiently characterized the pharmacokinetics of BTK inhibitors and triazole antifungals, and were used to predict untested clinical scenarios. Voriconazole exhibited the greatest influence on the exposures of BTK inhibitors. The dosage of zanubrutinib or acalabrutinib need to be reduced when co-administered with moderate CYP3A inhibitors.

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF THE COMBINATION OF IVACAFTOR AND LEFAMULIN IN PATIENTS WITH CYSTIC FIBROSIS

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF THE COMBINATION OF IVACAFTOR AND LEFAMULIN IN PATIENTS WITH CYSTIC FIBROSIS

AML-212 Older Adult Patient With AML and Limited Access to Drugs Achieves Complete Remission While Treated With Azacitidine, Low-Dose Venetoclax, and an Azole

Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an increasing incidence with age. Patients older than 65 years respond less to standard intensive chemotherapy and develop more treatment-related side effects. Therefore, treatment approaches are usually based on less intensive strategies, which provide brief overall survival (OS). Recently, it has been demonstrated that the addition of venetoclax, a BCL-2 inhibitor, to standard treatment may reinitiate apoptosis and lead to better outcomes. Venetoclax is metabolized by CYP3A. When administered with strong CYP3A inhibitors, such as azoles, the drug's concentration will increase 2- to 7-fold, empowering its effect. We will report, in what follows, the case of a weak 70-year-old patient with AML treated successfully with the combination of azacitidine and a modified dose of venetoclax due to inaccessibility and refunding issues; fluconazole was added to potentiate the effect of venetoclax in vivo, and the patient reached complete remission after four cycles of treatment. Given venetoclax's pharmacokinetics, CYP3A4 metabolization, and considering the inadequate accessible dose of venetoclax by the patient's third party along with the current Lebanese economic crisis, we decided to combine 200 mg of daily fluconazole, a moderate CYP3A4 inhibitor, to the pre-fixed low-dose venetoclax in order to increase its bioavailability in the patient's plasma and increase his chance of response. Schema extrapolated from the phase Ib sub-study evaluating the venetoclax-posaconazole interaction in untreated AML patients resulted in an ORR of 67%. In fact, the patient reached complete remission upon the end of the fourth cycle. He presented grade I febrile neutropenia after the first two cycles. No major adverse events were reported. To date, we believe that this is the first case described in the literature to report complete remission after combining low-dose venetoclax and azacitidine with a moderate CYP3A inhibitor.